Kreissman S.G.,Duke University |
Seeger R.C.,University of Southern California |
Matthay K.K.,University of California at San Francisco |
London W.B.,Harvard University |
And 13 more authors.
The Lancet Oncology | Year: 2013
Background: Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. Methods: Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. Findings: 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). Interpretation: Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma. Funding: National Cancer Institute and Alex's Lemonade Stand Foundation. © 2013 Elsevier Ltd.
Park J.R.,Fred Hutchinson Cancer Research Center |
Bagatell R.,Children's Hospital of Philadelphia |
London W.B.,Harvard University |
London W.B.,Childrens Oncology Group Statistics and Data Center |
And 4 more authors.
Pediatric Blood and Cancer | Year: 2013
Estimated 5-year survival rates for patients with non-high-risk and high-risk neuroblastoma are 90% and 50%, respectively. Recent clinical trials have shown excellent outcomes with reduced therapy for non-high-risk disease. For patients with high-risk neuroblastoma treated with chemoradiotherapy, surgery, and stem cell transplantation, the addition of anti-disialoganglioside (GD2) immunotherapy plus cytokines improves survival. Upcoming trials will study the incorporation of targeted radionuclide therapy prior to myeloablative chemotherapy into high-risk treatment. Phase 2 trials will investigate druggable target(s) including mTOR inhibition and GD2-directed therapy in combination with chemotherapy for patients with recurrent neuroblastoma, and ALK inhibition for those with ALK-aberrant tumors. © 2013 Wiley Periodicals, Inc.
Yu A.L.,University of California at San Diego |
Yu A.L.,Academia Sinica, Taiwan |
Gilman A.L.,Levine Childrens Hospital |
Ozkaynak M.F.,New York Medical College |
And 18 more authors.
New England Journal of Medicine | Year: 2010
BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P = 0.01) and overall survival (86±4% vs. 75±5% at 2 years, P = 0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. Copyright © 2010 Massachusetts Medical Society. All rights reserved.Results:With 61% of the number of expected events observed, the study met the criteria for early stopping of the randomization, on the basis of the superiority of immunotherapy over standard therapy with regard to event-free survival. The 2-year estimate for event-free survival was 66% in the immunotherapy group and 46% in the standard-therapy group. Immunotherapy was also superior to standard therapy with regard to the estimated rate of overall survival (86% vs. 75% at 2 years). The rate of event-free survival was significantly greater in the immunotherapy group than in the standard-therapy group (63% vs. 42% at 2 years). There was also a trend toward improved overall survival with immunotherapy as compared with standard therapy (84% vs. 76% at 2 years). The 2-year estimates for event-free survival and overall survival were 36% (16 events) and 76% (10 deaths, all disease-related), respectively in 25 patients nonrandomly assigned to receive immunotherapy. The event-free survival was worse in patients with disease of INSS stage 4 than in patients with disease of INSS stage 2, 3, or 4S. Diploidy was predictive of worse overall survival than hyperdiploidy. A complete or very good partial response, as compared with a partial response, before autologous stem-cell transplantation was predictive of improved event-free survival and overall survival. The treatment-group comparisons were not influenced by these factors. The effects of most interest reported in the immunotherapy group were pain, hypotension, capillary leak syndrome, and hypersensitivity reactions, with relatively few toxic effects in the standard-therapy group. Pain of grade 3 or 4 was noted in 52% of patients (during 25% of 598 cycles of immunotherapy). Pain reactions in the immunotherapy group were most frequent during cycle 1, occurring in 37% of patients, and decreasing to 14% during cycle 5. The most common site of pain was the abdomen. The capillary leak syndrome was reported in a total of 23% of patients, during 8% of immunotherapy cycles. It occurred more frequently during cycles 2 and 4, which involved Proleukin, with incidences of 11% and 13%, respectively, as compared with 3 to 7% during courses involving GM-CSF (cycles 1, 3, and 5). Grade 3 or 4 hypersensitivity reactions were reported in 25% of patients, during 15% of immunotherapy cycles. Hypersensitivity reactions were more frequent during the two cycles involving Proleukin, with incidences of 26% and 25%, as compared with 5 to 12% during the three cycles involving GM-CSF. Such reactions may be attributable to symptoms and signs that reflect both toxic effects of Proleukin and antibody-related hypersensitivity. Other toxic effects that were common during immunotherapy cycles included fever (39%), hypokalemia (35%), hyponatremia (23%), liver dysfunction (abnormal alanine aminotransferase level, 23%), hypotension (18%), diarrhea (13%), urticaria (13%), and hypoxia (13%). Early in the study, 2 patients were inadvertently given an overdose of the scheduled Proleukin due to a medication error; one of these patients died of Proleukin-related capillary leak and pulmonary edema. All other toxic effects were self-limited and resolved soon after the cessation of treatment and well before the beginning of the subsequent treatment.Patients:226 patients. Standard-therapy group (isotretinoin only): n=113, 4 were <18 months and 109 were ≥18 months. Immunotherapy group (6 cycles of isotretinoin and 5 concomitant cycles of ch14.18 in combination with alternating GM-CSF and Proleukin): n=113, 4 were <18 months and 109 were ≥18 months; 6 did not receive assigned intervention, having declined immunotherapy and received standard therapy. 25 patients (over 18 months of age) were nonrandomly assigned to receive immunotherapy because of biopsy-proven residual disease after autologous stem-cell transplantation. Follow-up: 4 days to 6.9 years (median 2.1 years). Dropouts: n=40 [23 on immunotherapy (17 due to side effects) and 17 on standard therapy].Indications:132 patients with refractory neuroblastoma [International Neuroblastoma Staging System stage (INSS): 2 (n=4), 3 (n=10), 4S (n=2), 4 (n=89) and unknown (n=8)].TypeofStudy:An open, randomized study evaluating whether adding Proleukin or granulocyte-macrophage colony-stimulating factor (GM-CSF) with monoclonal antibody ch14.18 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. NCT00026312.DosageDuration:3.0×106 IU per square meter daily was given in cycles 2 and 4 by means of continuous infusion, for 4 days during week 1, for 4 days during week 2 at 4.5×106 IU per square meter daily. Duration: 2 years. 2 patients were inadvertently given an overdose of the scheduled Proleukin (i.e., a dose >20 times the scheduled dose) due to a medication error.AdverseEffects:An unspecified number of patients had neuropathic pain, hypotension, hypoxia, fever without neutropenia, urticaria, infection (any), infection (catheter related), nausea, vomiting, diarrhea, hyponatremia, hypokalemia, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, hypercalcemia, serum sickness, seizure, central nervous system cortical symptoms (encephalopathy, confusion and psychosis). 12 (11%) patients in cycle 2 and 15 (13%) in cycle 4 had capillary leak syndrome; 29 (26%) and 28 (25%), respectively hypersensitivity reactions. 1 patient had drug intoxication characterized by capillary leak and pulmonary edema. 17 patients had adverse events leading to withdrawal.FreeText:Primary endpoint: event-free survival. Secondary endpoint: overall survival. Tumor MYCN status: 52 were not amplified, 36 amplified and 25 unknown. Tumor histologic features: 4 were favorable, 68 unfavorable and 41 unknown. Tumor ploidy: 49 were hyperdiploid, 35 diploid and 29 unknown. 28 patients had ≥1 purged stem cell infusions. Response before autologous stem cell transplantation (ASCT): 40 complete response, 47 very good partial response and 26 partial response. 107 patients had 1 ASCT and 6 had 2 ASCTs. In nonrandomized patients, 23 had INSS stage 4 disease; 6 tumors showed MYCN amplification, 16 had unfavorable histologic features, 12 were diploid, 21 had a partial response before ASCT and only 1 had undergone 2 autologous stem-cell transplantations. Patients had induction therapy, ASCT, and radiotherapy. The monoclonal antibody ch14.18 was given in cycles 1 through 5; GM-CSF was given in cycles 1, 3, and 5; and isotretinoin was given during the last 2 weeks in each of the five cycles and also given by itself during a final 6th cycle. Concomitant drugs: isotretinoin at a dose of 160 mg per square meter daily, monoclonal antibody ch14.18 at a dose of 25 mg per square meter daily for 4 consecutive days.AuthorsConclusions:In summary, the addition of ch14.18, GM-CSF, and interleukin-2 to isotretinoin therapy was associated with improved event-free and overall survival among children with high-risk neuroblastoma who had a response to initial chemotherapy and received immunotherapy within 100 days after autologous stem-cell transplantation. Our data suggest that more routine use of this immunotherapy regimen for such patients may be beneficial. Future avenues of investigation include developing more effective and less toxic ways to stimulate ch14.18-mediated antibody-dependent cell-mediated cytotoxicity and identifying more efficacious GD2-targeted monoclonal antibodies or genetically modified constructs targeting GD2.
Matloub Y.,Case Western Reserve University |
Bostrom B.C.,Childrens Hospitals and Clinics of Minnesota |
Hunger S.P.,Aurora University |
Stork L.C.,Oregon Health And Science University |
And 16 more authors.
Blood | Year: 2011
Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS. © 2011 by The American Society of Hematology.
Sepe D.M.,Children's Hospital of Philadelphia |
Sepe D.M.,University of Pennsylvania |
Mcwilliams T.,Children's Hospital of Philadelphia |
Chen J.,University of Pennsylvania |
And 10 more authors.
Pediatric Blood and Cancer | Year: 2012
Background: Recent studies suggest that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine polymorphic variants of genes and relapse risk, toxicity, and drug dose delivery in standard risk ALL. Procedure: We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children's Cancer Group ALL study, CCG-1891. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually and clique-finding methodology was employed for detection of significant gene-gene interactions. Results: After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR=1.94, P=0.047), MTHFR (HR=1.61, P=0.034), MTRR (HR=1.95, P=0.01), and TS (3R/4R, HR=3.69, P=0.007) were found to significantly increase relapse risk. One gene-gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons (P=0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes. Conclusions: These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene-gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. childhood ALL therapy. © 2011 Wiley Periodicals, Inc.
Pressey J.G.,Children's Hospital of Philadelphia |
Anderson J.R.,Childrens Oncology Group Statistics and Data Center |
Crossman D.K.,University of Alabama at Birmingham |
Lynch J.C.,Childrens Oncology Group Statistics and Data Center |
Barr F.G.,University of Pennsylvania
Pediatric Blood and Cancer | Year: 2011
Background: Aberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell carcinoma, medulloblastoma, and rarely, rhabdomyosarcoma (RMS). A previous report utilizing in situ hybridization has provided initial evidence for the expression of Hh targets GLI1 and PTCH in RMS tumors. Procedure: To investigate the role of Hh pathway signaling in pediatric RMS and undifferentiated sarcoma (US) tumors, the expression of Hh pathway targets GLI1 and PTCH was measured. RNA was extracted from archival human tumor specimens collected from pediatric patients enrolled on Intergroup Rhabdomyosarcoma Study III and IV, and subjected to quantitative reverse transcriptase-polymerase chain reaction. Results: Expression of GLI1 with or without PTCH was detected in substantial subsets of embryonal RMS (ERMS) and US tumors but only rarely in alveolar RMS tumors. Neither PTCH mutations nor activating SMO mutations were detected in ERMS tumors with high GLI1 expression. Microarray analysis demonstrated relative overexpression of downstream Hh targets in ERMS tumors with high or intermediate GLI1 expression. Unlike a recent report, Hh pathway activity in ERMS tumors did not correlate with a unique clinical phenotype. Conclusions: Our findings support a role for Hh pathway activation in the genesis of a subset of ERMS and US tumors. Hh signaling may represent a novel therapeutic target in affected tumors. © 2011 Wiley-Liss, Inc.
Villablanca J.G.,University of Southern California |
London W.B.,Harvard University |
London W.B.,Childrens Oncology Group Statistics and Data Center |
Naranjo A.,Childrens Oncology Group Statistics and Data Center |
And 16 more authors.
Clinical Cancer Research | Year: 2011
Purpose: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Experimental Design: Patients received 7 days of fenretinide: 2,475 mg/m 2/d divided TID (<18 years) or 1,800 mg/m 2/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). Results: Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible. Conclusions: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies. ©2011 AACR.
Stricker T.P.,Vanderbilt University |
Morales La Madrid A.,University of Chicago |
Morales La Madrid A.,Hospital Sant Joan Of Deu |
Chlenski A.,University of Chicago |
And 20 more authors.
Molecular Oncology | Year: 2014
Microarray-based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high-quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin-fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high-throughput digital system to assay the expression of genes in an "ultra-high risk" microarray classifier in FFPE high-risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi-gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high-risk neuroblastoma samples using the NanoString nCounter™ Analysis System. For classification of each patient, the Pearson's correlation coefficient was calculated between the standardized nCounter™ data and the molecular signature from the microarray data. We demonstrate that the nCounter™ 42-gene panel sub-stratified the high-risk cohort into two subsets with statistically significantly different overall survival (p=0.0027) and event-free survival (p=0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounter™ System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high-risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high-risk neuroblastoma patients using FFPE tumor samples and the nCounter™ System are warranted. © 2014 Federation of European Biochemical Societies.
Delgado D.C.,University of Wisconsin - Madison |
Hank J.A.,University of Wisconsin - Madison |
Kolesar J.,University of Wisconsin - Madison |
Lorentzen D.,University of Wisconsin - Madison |
And 14 more authors.
Cancer Research | Year: 2010
Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific FcγR alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the FcγR2A 131-H/H genotype showing a higher response rate than other FcγR2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response. ©2010 AACR.